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Schwann Cell Myelination

James L. Salzer

Department of Neuroscience and Physiology, New York University Neuroscience Institute, New York University School of Medicine, New York, New York 10016 Correspondence: [email protected]

Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between axons and Schwann cells. Extrinsic signals from the axon, and the extracellular matrix, drive Schwann cells to adopt a myelinating fate, whereas myelination reorganizes the axon for its role in conduction and is essential for its integrity. Here, we review our current under- standing of the development, molecular organization, and function of myelinating Schwann cells. Recent findings into the extrinsic signals that drive Schwann cell myelination, their cognate receptors, and the downstream intracellular signaling pathways they activate will be described. Together, these studies provide important new insights into how these pathways converge to activate the transcriptional cascade of myelination and remodel the actin cyto- skeleton that is critical for morphogenesis of the myelin sheath.

he myelin sheath is a vertebrate evolutionary skeletal changes that direct glial membrane Tadaptation that likely enabled development wrapping around axons differ. In accordance, of large, complex nervous systems by promot- diseases of myelin, generally, are restricted to ing rapid, efficient nerve conduction. Based on those that affect PNS myelinated fibers (e.g., the appearance during evolution of several key CMT1) or CNS fibers (e.g., multiple sclerosis proteins, myelin is thought to have evolved in [MS], leukodystrophies, etc.). early gnathostomes in a common glial precur- Here, we focus on the myelinating Schwann sor, which later gave rise to the distinct Schwann cell. Its organization into discrete membrane cell and oligodendrocyte lineages (Gould et al. and cytoplasmic compartments will be de- 2008; Zalc et al. 2008). Indeed, the overall orga- scribed. New insights into the extrinsic signals nization of myelinated axons in the central and intracellular pathways that drive Schwann nervous system (CNS) and peripheral nervous cell myelination will be highlighted, including system (PNS) is similar, consistent with their pathways that regulate the actin cytoskeleton conserved roles in saltatory conduction. How- during myelin morphogenesis and the tran- ever, there are substantial differences in the de- scriptional cascade of myelination. Finally, ef- velopment and assembly of myelin by Schwann fects of myelinating Schwann cells on axons cells and oligodendrocytes. Thus, the extrinsic will be discussed. Several excellent reviews on signals that drive myelination, the transcrip- Schwann cell biology have recently been pub- tional cascades they activate, and even the cyto- lished (Pereira et al. 2012; Glenn and Talbot

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J.L. Salzer

2013b; Kidd et al. 2013) and may be consulted nodal, paranodal, juxtaparanodal, and inter- for additional details not provided here. nodal compartments. Radial polarity is indicat- ed by the distinct inner (adaxonal) and outer (abaxonal) membrane surfaces, which are pres- ORGANIZATION AND POLARITY OF THE ent at each end of the cell on opposite sides; PNS MYELIN SHEATH interposed between these two membranes do- Myelinating Schwann cells are radially and lon- mains are the compacted membranes of the my- gitudinally polarized cells (Salzer 2003; Ozcelik elin sheath. et al. 2010; Pereira et al. 2012). With myeli- The adaxonal membrane is separated from nation, Schwann cells organize into distinct the axolemma by a gap of 15 nm (the peri- membrane domains, each with a unique array axonal space); it is enriched in adhesion mole- of proteins, and a communicating set of cyto- cules and receptors that mediate interactions plasmic compartments (Fig. 1). Longitudinal with cognate ligands on the axon. These main- polarity is evident by the overall organization tain the periaxonal space and transduce signals of the myelinating Schwann cell, and axon, into from axonal growth factors, respectively. The

Basal lamina Abaxonal membrane Abaxonal membrane Apposition Cajal band Microvilli Apposition Cytoplasmic SN collars Adaxonal SN membrane SLI Paranodal junction Paranodal collar Compact myelin

Node

Periaxonal space Microvilli Junctional complex SLI Gap Juxtaparanode junction

Adaxonal membrane

Figure 1. Organization of myelinating Schwann cells. Schematic organization of myelinating Schwann cells (blue) surrounding an axon (gray); the left cell is shown in longitudinal cross section and the right cell is shown unwrapped. Myelinating Schwann cells are surrounded by a basal lamina (illustrated only on the left), which is in direct contact with the abaxonal membrane. The abaxonal compartment contains the Schwann cell nucleus (SN); it is divided into Cajal bands and periodic appositions that form between the abaxonal membrane and outer turn of compact myelin. The Schwann cell adaxonal membrane is separated from the axonal membrane by the periaxonal space (shown in yellow). Compact myelin is interrupted by Schmidt–Lanterman incisures (SLI), which retain cytoplasm and are enriched in the gap and other junctions; a similar autotypic junctional complex of adherens, tight and gap junctions, forms between the apposed membranes of the paranodal loops. Also shown are the paranodal loops and junctions (red) and the Schwann cell microvilli contacting the axon at the node. The axon diameter is reduced in the region of the node and paranodes. (This figure is adapted, with permission, from an original figure in Salzer 2003; modified in Nave 2010.)

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Schwann Cell Myelination

adaxonal membrane is further organized into sheath (Fig. 2). These appositions are enriched the paranodal, juxtaparanodal, and internodal in a dystroglycan complex linked via dystro- domains. The largest such domain is the inter- phin-related protein 2 (Drp2) to periaxin, a node, comprising some 99% of the length of highly abundant scaffolding protein of myeli- the myelinating Schwann cell. Glial adhesion nating Schwann cells (Sherman et al. 2012b). molecules present along the internode include These appositions delineate a network of anas- the myelin-associated glycoprotein (MAG) and tomosing, cytoplasmic channels, termed Cajal the nectin-like proteins, Necl-2 (CADM1) bands (Court et al. 2004). These cytoplasmic and Necl-4 (CADM4) (Maurel et al. 2007; Spie- channels lie on the outside of the Schwann cell gel et al. 2007); the Necls/Cadm are tethered to and provide a conduit for centrifugal transport a 4.1-G-based cytoskeleton. The remaining 1% of RNA and proteins originating in the cell corresponds to the nodal region, including the soma en route to the paranodal collar (Gould node itself, the flanking paranodes, and juxta- and Mattingly 1990; Court et al. 2004). The out- paranodes. Protein components for these do- er membrane of the Cajal bands interact with mains are discussed in detail elsewhere (Salzer laminin of the basal lamina via the b1 integrin et al. 2008; see also Rasband and Peles 2015). (Court et al. 2011b) and a second, distinct dys- The outer, abaxonal membrane lies adjacent troglycan complex (Masaki and Matsumura to and mediates interactions with laminin in 2010; Walko et al. 2013). Consistent with their the basal lamina, notably the integrins, includ- proposed role in transport, Cajal bands are en- ing a6b1, which is expressed initially, and a6b4 riched in a large array of cytoskeletal proteins, and b dystroglycan, which are up-regulated including microtubules, intermediate filaments, with myelination (Einheber et al. 1992; Previtali and an actin/spectrin complex (Susuki et al. et al. 2003). Unlike the inner cytoplasmic com- 2011; Kidd et al. 2013; Walko et al. 2013). They partment, which is uniformly spaced, the outer also represent sites of localized protein synthesis cytoplasmic compartment is interrupted by pe- (Gould and Mattingly 1990), and intracellular riodic appositions between the abaxonal mem- signaling via laminin receptors (Heller et al. brane and the outer wrap of the compact myelin 2014). Based on their enrichment in caveolae

Figure 2. Cajal bands. Fluorescence micrograph showing a portion of a teased, myelinated fiber from adult rat sciatic nerve, the presence of the Cajal bands (green), and the membrane appositions (red) in the abaxonal compartment. Staining shown is for phospho-NDRG1 (green) and a-dystroglycan (red) (see Heller et al. 2014 for further details).

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(Mugnaini et al. 1977; Koling 1985; Mikol et al. these proteins is as yet incomplete, including 1999), they may function in the uptake of me- whether they are localized to compact myelin tabolites from the extracellular space. or to other sites in the Schwann cell. In between these two membranes is the Compact myelin is interrupted by the multilamellar, compact myelin sheath, which re- Schmidt–Lanterman incisures, which are inter- sults from the circumferential wrapping of the spersed along the internode and most abundant Schwann cell plasma membrane. Myelin pro- in heavily myelinated, large-diameter fibers. vides a high-resistance, low-capacitance sheath Surprisingly, the clefts often develop after the essential for impulse propagation by saltatory myelin sheath has substantially formed, aris- conduction. The myelin sheath itself is com- ing via extension from the inner or outer collars prised of 40 or more lamellae (Peters et al. of cytoplasm by circumferential extension into 1991). Electron micrographs of compact myelin compact myelin sheath (Small et al. 1987), in- reveal interperiod lines, which represent the ap- dicating an active process of decompaction of positions of the extracellular leaflets, alternat- the myelin lamellae. Their late origin suggests ing with majordense lines (MDLs), representing that they do not have an essential role during the tight apposition of the cytoplasmic leaflets PNS myelin formation, but rather may assist in (Fig. 3). Myelin has a uniquely high- (70%) its maintenance; this notion is consistent with lipid content for a plasma membrane and is periaxin mutants that lack clefts and form un- enriched in galactosphingolipids, saturated stable myelin sheaths (Gillespie et al. 2000). long-chain fatty acids and, particularly, choles- The clefts have long been thought to pro- terol; the latter has an essential role for myelin vide a conduit for communication between sheath assembly (Saher and Simons 2010). the inner and outer collars of cytoplasm via Compact myelin is greatly enriched in a very the presence of gap junctions, which are arrayed few proteins (Fig. 3); these are likely to be quite between adjacent membranes (Balice-Gordon stable in the mature sheath with limited turn- et al. 1998). Adjacent membranes in the clefts over akin to the stability of CNS myelin proteins also harbor autotypic adherens junctions (Fan- (Toyama et al. 2013). Among these proteins are non et al. 1995), tight junctions, and a series of P0, a transmembrane adhesion molecule of the PDZ (PSD95, Dlg1, ZO-1)-domain-containing immunoglobulin gene superfamily, which pro- proteins, including the MAGUKs, which are motes apposition of the extracellular leaflets via linked to the 4.1G cytoskeleton (Terada et al. homophilic adhesion (Filbin et al. 1990; Shapiro 2012), and likely, thereby, to F-actin in the clefts et al. 1996). P0 requires cholesterol for proper (Trapp et al. 1989). Recent studies suggest that endoplasmic reticulum (ER) export (Saher et the clefts, which are enriched in the tyrosine al. 2009). Another key protein is maltose-bind- kinase Src (Terada et al. 2013), are a site of au- ing protein (MBP), a peripheral membrane pro- tocrine signaling (Heller et al. 2014), consistent tein thought to neutralize the charges of the with their rich array of cell junctions. Many phospholipids, especially phosphatidylserines of the adhesion molecules present in the adaxo- (Kidd et al. 2013). MBP and the cytoplasmic nal membrane, that is, MAG and the Necls segment of P0, together, promote apposition (Cadms), are also enriched in the clefts (Maurel of the intracellular leaflets to form the MDL et al. 2007; Spiegel et al. 2007), suggesting a (Martini et al. 1995). Other compact myelin common topology; interactions of the Cadms proteins include several tetraspanins, notably likely contribute to the structural integrity of PMP22, which is frequently mutated in inherit- the incisures. ed neuropathies (Vallat et al. 1996; Rossor et al. Components of classical polarity complexes 2013). Recent mass spectroscopy studies, using are enriched at distinct sites of myelinating myelin-enriched fractions, suggest the presence Schwann cells (Masaki 2012; Pereira et al. of many additional proteins, some known and 2012). Notably, Par-3 is enriched in the inner, others novel (Patzig et al. 2011). These are pre- periaxonal cytoplasmic compartment and in sent at much-reduced levels; characterization of the incisures (Poliak et al. 2002; Chan et al.

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Schwann Cell Myelination

Uncompacted

Compacted

P0

+++ MBP Intraperiod line

Cytoplasm +++ +++ Major dense line

+++

Extracellular space

PMP22

Figure 3. Schematic organization of the compact myelin sheath. Myelin forms, initially, as loose wraps of uncompacted membrane. With the onset of myelin transcription, myelin proteins are up-regulated, including P0, maltose-binding protein (MBP), and PMP22, which are shown diagrammatically. Compaction is mediated by extracellular interactions of P0 tetramers on one membrane interacting with P0 tetramers on the opposing membrane, shown here only as dimer/dimer interactions for simplicity. Compaction of the cytoplasmic leaflets is mediated by electrostatic interactions of MBP with the phospholipid bilayer supplemented by the interactions with the cytoplasmic tail of P0. Compact myelin appears on electron microscopy (EM) as a major dense line (MDL) (representing tight apposition of the cytoplasmic leaflets) alternating with the intraperiod lines (rep- resenting the two apposed extracellular leaflets) as shown.

2006). Par-3 is part of the PAR-3/PAR-6/aPKC nents of these polarity complexes are also complex, which is typically enriched in cell expressed in myelinating Schwann cells, mem- junctions; it is the first polarity complex to be- bers of the Scribble complex are enriched in come asymmetrically localized in epithelia and the abaxonal compartment and Crumbs is en- regulates the localization of other polarity com- riched, together with Par-3, in the adaxonal plexes (Goldstein and Macara 2007). These oth- domain and SLI (Poliak et al. 2002; Chan et al. er complexes include the Scribble/Lethal giant 2006; Ozcelik et al. 2010). This organization, larvae (Lgl)/Discs large (Dlg) complex and the together with location of the extracellular ma- crumbs/Pals/Patj complex; in polarized epithe- trix, has evoked metaphors to polarized epithe- lia, these have a basolateral and apical localiza- lia and to the notion that the adaxonal and tion, respectively (Pereira et al. 2012). Compo- abaxonal compartments are functional ortho-

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J.L. Salzer

logs of apical and basolateral domains, respec- Krox20 are up-regulated and/or activated (Sva- tively (Salzer 2003; Pereira et al. 2012). ren and Meijer 2008; Kao et al. 2009; He et al. Components of these polarity complexes 2010). NF-kB was implicated in regulating mye- have been implicated in myelin formation. lination in vitro (Nickols et al. 2003); it has a Thus, Schwann cells fail to myelinate sensory dispensable role in vivo (Morton et al. 2013). neurons in cocultures when Par3 is knocked During the transition from promyelination to down by small hairpin RNA (shRNA) (Chan et myelination, Pou3f1 and Pou3f2 are turned off al. 2006), and defects of myelination are ob- and Krox20 is up-regulated. Krox20 expression served when the activity of aPKC, which is reg- is promoted by Pou3f1 and Pou3f2 (Jaegle et al. ulated by Par3, is likewise reduced (Beirowski 2003) and NFATc4and YY1 (Kao et al. 2009; He et al. 2011). The precise mechanisms that drive et al. 2010). Sox10 also drives Krox20 expression, the targeting of these complexes to their respec- cooperatively with NFATc4(Kao et al. 2009) and tive intracellular sites, regulate their activity, by recruiting the Mediator12 complex, a regula- their importance during myelination in vivo, tor of transcription initiation and elongation, and the identity of their downstream effectors to the Schwann cell-specific myelin-specific en- are significant questions for future study. hancer (MSE) of the Krox20 gene (Weider et al. 2012; Vogl et al. 2013). Another Pou domain TF, Pou6F1 (Brn5), is expressed in myelinating TRANSCRIPTIONAL AND EPIGENETIC Schwann cells (Wu et al. 2001); its function in REGULATION OF THE MYELIN PHENOTYPE promoting or maintaining the myelinating phe- The myelin phenotype results from a sequential, notype has not yet been established. Finally, in feedforward cascade of promyelinating tran- keeping with the massive up-regulation of lipid scription factors (TFs) (see Fig. 4) (Svaren and synthesis during myelination, sterol regulatory Meijer 2008). These TFs include Sox2, NF-kB, element-binding protein (SREBP, TFs) are up- and Egr1, which are expressed initially. With regulated and have an essential role in Schwann segregation of axons and myelination, NF-kB, cell myelination (Camargo et al. 2009). Pou3f1 (Oct6/SCIP/Tst1), Pou3f2 (Brn2), Krox20 is considered a master regulator of Sox10, NFATc4, YY1 (Yin Yang), and Egr2/ PNS myelination as, together with the NAB

Sox10 NFATc4 Sox10 Hdac1/2 YY1 Krox20 sox10 Pou3f1 Nab1/2 NF-κB Pou3f2 SREBP Immature Promyelinating Myelinating

Axon Myelinated axon Nucleus Schwann cell

Figure 4. Transcriptional cascade of myelination. Expression of TFs at different stages of the Schwann cell lineage is shown. At the immature stage, expression of Sox10 and of Hdac1/2 (epigenetic regulators, red) is essential for progression to the promyelinating stage; NF-kB promotes, but is not essential, during the Schwann cell lineage. Progression from the promyelinating to the myelinating phenotype requires Pou3f1 (Oct6) and Pou3f2 (Brn2) for timely advance; Sox10, NFATc4, and YY1 are essential. These latter proteins all promote expression of Krox20, which, together with the interacting Nab proteins, is essential for the expression of the myelinating phenotype. Lipid biosynthesis is up-regulated via SREBP.

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Schwann Cell Myelination

proteins, it drives transcription of myelin struc- myelination in synergy with Sox10 (Jacob et al. tural proteins and biosynthetic components of 2011); the combined loss of HDAC1 and -2 re- myelin lipid synthesis (Topilko et al. 1994; Le sults in the arrest of Schwann cells at the pro- et al. 2005b). A striking feature of the transcrip- myelinating stage (Jacob et al. 2011). Finally, tional phenotype of a Schwann cell is that it can miRNAs have been implicated as important, adopt alternate fates as a myelinating versus a posttranscriptional regulators of myelination nonmyelinating/Remak Schwann cell. This bi- (Pereira et al. 2012). This is compellingly indi- nary distinction is reinforced via transcriptional cated by conditional inactivation of DICER in cross-repression in which Sox2 and c-Jun inhib- Schwann cells during development, which re- it Krox20 expression, and vice versa (Le et al. sults in the arrest of Schwann cells at the pro- 2005a; Parkinson et al. 2008; Jessen et al. 2015). myelinating stage (Bremer et al. 2010; Pereira Maintenance of the myelinating phenotype re- et al. 2010; Yun et al. 2010). An important ques- quires the ongoing expression of both Krox20 tion is the identity of the extrinsic signals that and Sox10; conditional inactivation of either drives this transcriptional program, and that of results in dedifferentiation, which is particular- axon wrapping. ly rapid in the case of Krox20 (Decker et al. 2006; Bremer et al. 2011). This latter result sug- EXTRINSIC SIGNALS THAT REGULATE gests an active transcriptional cascade involving MYELINATION: LIGANDS AND RECEPTORS Sox10, likely functioning with Pou3f1 and/ or Pou3f2, to sustain Krox20 expression; these There has been substantial progress in identi- results also imply Krox20 is subject to active fying the extrinsic signals, their Schwann cell turnover. receptors, and the intracellular pathways they Recent studies highlight the importance of regulate that control myelination (Fig. 5). The epigenetic regulation during PNS myelination major and best-characterized extrinsic signals (Pereira et al. 2012), similar to its essential are those presented by the axon and extracellu- role in the CNS (Huynh and Casaccia 2013). lar matrix, that is, neuregulin (NRG) type III Epigenetic modifications that regulate gene ex- and laminin, respectively. Other key signals pression include DNA methylation, posttrans- and receptors that are essential for PNS mye- lational modifications of nucleosomal histones lination were more recently identified and (e.g., acetylation, methylation, citrullination, include G-coupled protein (Gpr) 126 and etc.), and expression of noncoding RNAs, no- Adam22/Lgi4 (Salzer 2012; Glenn and Talbot tably microRNAs (miRNAs) (Huynh and Ca- 2013b). In general, there appears to be a spatio- saccia 2013). In the case of Schwann cells, sev- temporal transition in signals with those origi- eral epigenetic modifiers work in concert with nating from the axon, that is, NRG1, activating Sox10, including the Brahma-associated factor the adaxonal compartment early on, and those (BAF) complex, a chromatin-remodeling com- that originate in basal lamina, for example, lam- plex that regulates access to DNA (Weider et al. inins and collagens, which activate the abaxonal 2013). Loss of Brahma-related gene product compartment acting with, perhaps, a modest (Brg1), the catalytic core of BAF, phenocopies delay (Heller et al. 2014). This is consistent Sox10 conditional knockouts (Finzsch et al. with earlier studies showing that axonal signals 2010). Sox10 appears to direct the Baf60a-de- direct Schwann cell assembly of the basal lamina pendent recruitment of BAF complexes to sev- during development (Bunge et al. 1982). eral Sox10 target genes, including Oct6 and Krox20 and thereby enhancing their expression Axonal Regulation of Myelination: NRG1 (Weider et al. 2013). Sox10 also interacts with and erbB Receptors histone deacetylases (HDACs)—enzymes that remove acetyl residues from lysines in histones It has been known for more than 100 years that thereby regulating transcription. In particular, axons direct their own ensheathment fate, that HDAC2 activates the transcriptional program of is, whether Schwann cells ensheath multiple,

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Abaxonal Abaxonal: Cajal band Abaxonal: Apposition Basal lamina Basal lamina LN2 LN2 LN2 ? α α6β1 Gpr126 β DG α6β4 α6β1 FAK Rac cAMP PI3K PKA Sgk1 Myosin II Profilin 1 Compact DRP2 Pou3f1 myelin Periaxin

Cajal band

Premyelinating Myelinating Apposition Adaxonal

Nrg1 Nrg1 Adam22

+BACE Lgi4 23 –TACE Dlg1 ? γ cdc42 SSH1 PLC- Ras PI3K PTEN N-WASP Cofilin Ca2+/CnB MAPK Akt

Arp2/3 Actin NFAT yy1 mTOR REDDI Krox20 Cytoskeleton Transcription Translation

Figure 5. Schematic of extrinsic signals, receptors, and intracellular signaling pathways that regulate myelination. This figure summarizes the key extrinsic signals, their receptors, and the downstream signaling pathways active in the adaxonal and abaxonal compartments. The major axonal signals include type III NRG1 and Adam22 (disintegrin and metalloprotease), which signal via erbB receptors and Lgi4 (leucine-rich glioma inactivated), respectively. NRG1 is subject to protease cleavage that is activating (BACE, b-secretase) or inactivating (TACE, tumor necrosis factor–a-converting enzyme). Major pathways downstream from erbB signaling include (1) phospholipase C (PLC)-g, calcineurin B (CnB), and nuclear factor of activated T cells (NFAT), (2) mitogen- activated protein kinase (MAPK), and (3) PI3K, Akt, and the mammalian target of rapamycin (mTOR). NFATc4 and YY1 drive transcription of Krox20; mTOR is a regulator of cap-dependent protein synthesis. NRG signal- ing also drives the remodeling of the actin cytoskeleton as shown. In the abaxonal compartment before myeli- nation, laminin signaling activates FAK and Rac to promote radial sorting. Gpr126 regulates cAMP and protein kinase A (PKA) to promote sorting and myelination; its assignment to the abaxonal compartment is tentative and its ligand(s) at the time of this review has not been reported. With maturation, the abaxonal compartment organizes into the cytoplasmic channels, termed Cajal bands, and membrane appositions. Signaling in the Cajal bands is mediated in part via integrins. The membrane apposition is mediated by a complex of dystroglycan, DRP2, and periaxin; the space between the baseline (BL) and the appositions as shown is exaggerated for artistic purposes. See the text for additional details on these pathways. N-WASP,Neuronal Wiskott–Aldrich syndrome protein.

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small axons or segregate and myelinate larger also been implicated in the segregation of axons ones (Langley and Anderson 1903). Myelina- by Schwann cells (Taveggia et al. 2005; Raphael tion typically commences around axons that et al. 2011). The first indication that NRG1 is are 1 mm in size (Peters et al. 1991), in agree- also required for myelination was the hypomye- ment with theoretical models that suggest mye- lination of peripheral nerves when NRG1 recep- lination enhances conduction velocity in PNS tors were conditionally inactivated during late axons with diameters 1 mm (Rushton 1951). Schwann cell development (Garratt et al. 2000). Above this size, myelin sheath thickness and in- Subsequently, it was shown that the expres- ternodal length and, thus, the total myelin mem- sion levels of type III NRG1, an abundant mem- brane expanse, are tightly correlated to the di- brane-tethered isoform on axons, correlate with ameter of the axon (Matthews 1968). For sheath the ensheathment fate of axons; thus, axons that thickness, this relationship is measured as the g will be myelinated express much higher levels of ratio, that is, axon diameter/total fiberdiameter, type III NRG1 than do axons in Remak fibers which is typically close to 0.67 for PNS fibers. (Taveggia et al. 2005). Importantly, forced ex- Thus, axons not only trigger Schwann cells to pression of type III NRG1 in sympathetic fibers, myelinate, but also determine the amount of which are normally unmyelinated, resulted in myelin they form. their myelination in vitro (Taveggia et al. These considerations led to the hypothesis 2005). Haploinsufficiency or full genetic inacti- that a critical axonal diameter triggers Schwann vation of NRG1, in particular of the type III cell myelination, reflecting either the size of the isoform, resulted in significant PNS hypomye- axon (Murray 1968; Friede 1972; Voyvodic 1989) lination (Michailov et al. 2004; Taveggia et al. or the quantity of signaling molecules on its 2005; Brinkmann et al. 2008), a reduction in the surface (Spencer and Weinberg 1978). Alterna- percentage of myelinated axons and aberrant tively, distinct biochemical signals presented by sorting in Remak fibers (Taveggia et al. 2005). the axon may dictate its ensheathment fate (Sal- Finally, overexpression of the type III isoform in zer 1995). Work in recent years indicates that neurons results in significant hypermyelina- axons destined for myelination are both larger tion, with substantially reduced g ratios (Mi- and biochemically distinct as they express high- chailov et al. 2004). er levels of the growth factor, NRG1, which is a Together, these results indicate that type III key trigger for myelination (Nave and Salzer NRG1 is an instructive signal; threshold levels 2006). trigger Schwann cell myelination, and, above NRG1 is a member of the epidermal growth that threshold, the amount of compact myelin factor (EGF) superfamily, comprised of a large formed is graded to the levels of type III NRG1. number of alternatively spliced transmembrane As NRG type III also controls Schwann cell isoforms. Six major classes of NRG1 have been proliferation and survival, elevated levels of described (types I–VI), which differ in the splic- NRG1 type III drive generation of the addition- ing patterns of the ectodomain; types I–III al Schwann cells required for myelination, are the most abundant, with type III being the thereby coordinating Schwann cell numbers to predominant form on peripheral axons (Mei their myelinating fate (Taveggia et al. 2005). and Xiong 2008). NRG1, like other members Once myelination is complete, ongoing of the EGF superfamily, signals by binding signaling from axonal NRG1 or erbB receptors to and activating members of the erbB family is not required to maintain the myelin sheath of tyrosine kinase receptors (Mei and Xiong (Atanasoski et al. 2006; Fricker et al. 2011). This 2008). Schwann cells principally express the notion agrees with the rare “double” myelin erbB2/erbB3 heterodimer (Newbern and Birch- sheaths found in the sympathetic trunk in meier 2010). which the outer myelin sheath is displaced NRG1 signaling regulates virtually all as- from contact with the axon, but continues to pects of the Schwann cell lineage (Newbern be maintained (Heath et al. 1991). After injury, and Birchmeier 2010; Jessen et al. 2015). It has axonal NRG is surprisingly dispensable, al-

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though it does promote timely remyelination preciation of its role in myelination resulted (Fricker et al. 2013; Stassart et al. 2013). This from investigations of the spontaneous, reces- reflects the up-regulation and secretion of a sive mutation claw paw (clp), which results in soluble NRG isoform by Schwann cells, which PNS-specific hypomyelination (Henry et al. functions as an autocrine signal that is necessary 1991). Positional cloning showed that clp arises and sufficient to promote remyelination (Stas- from an insertion in the Lgi4 gene, leading to a sart et al. 2013). These findings raise the possi- mutant Lgi4 protein that lacks exon 4 (Berming- bility that administration of soluble NRG1 may ham et al. 2006). Subsequent studies showed enhance repair in some settings. that Lgi4 is secreted by Schwann cells and binds All NRG1 isoforms, including type III, are in a paracrine fashion to Adam22 axons. These cleaved by metalloproteinases just extracellular interactions are necessary for Schwann cells to to the plasma membrane (Falls 2003). This advance beyond the promyelinating stage (Kegel cleavage releases the ectodomain from the type et al. 2013). Panknockouts of Adam22 (Sagane I and II isoforms, which then function as para- et al. 2005), Schwann cell–specific deletion of crine signals. In contrast, the type III isoform Lgi4, or neuron-specific deletion of Adam22 has a second, amino-terminal hydrophobic se- (Ozkaynak et al. 2010) all result in major defects quence and is, therefore, retained on the axon of myelination. The mechanism(s) by which membrane after cleavage, functioning as a jux- Lgi4–Adam22 interactions promote myelina- tacrine signal (Falls 2003; Taveggia et al. 2005). A tion is a key, unresolved question, including variety of metalloproteinases have been impli- whether binding of Lgi4 to Adam 22 on the cated in NRG1 cleavage (Shirakabe et al. 2001; axon converts this axonal protein to a promyeli- Horiuchi et al. 2005; Luo et al. 2011b), includ- nating signal (by modifying its confirmation or ing BACE and TACE (also called ADAM17). associationwith otheraxonal proteins) oraffects Cleavage by these proteases has opposing func- other axonal proteins that interact with the tional effects. BACE cleavage activates NRG1 Schwann cell. Interestingly, Lgi4–Adam22 in- and is required for normal myelination; mice teractions have distinct roles at other stages of deficient in this enzyme are hypomyelinated in the lineage. Thus, Lgi4 is required for the prolif- both the PNS and CNS (Hu et al. 2006; Willem eration of glial-restricted progenitors, but not et al. 2006). In contrast, TACE cleavage inacti- Schwann cells (Nishino et al. 2010), and, in the vates NRG1, and mice with conditional loss of mature myelinated fiber, it functions as part of TACE are hypermyelinated (La Marca et al. the juxtaparanodal complex (Ogawa et al. 2010). 2011). Dual cleavage by both TACE and BACE may release the type III ectodomain, allowing The Basal Lamina: Laminin and Laminin it to function as a paracrine signal (Fleck et al. Receptors 2013). Although NRG1 is the likely substrate that accounts for these protease effects on mye- Extracellular matrix components, including lination, it is also possible that other protein laminin, are synthesized by the Schwann cell substrates at the membrane surface (Hogl et al. and function as critical autocrine signals essen- 2013) may also be involved. Together, these re- tial for ensheathment and myelination (Bunge sults suggest that competition between secre- et al. 1986; Chernousovet al. 2008). Evidence for tases may regulate the extent of myelination. the key role of laminin was initially suggested by Thus, modulating NRG1 cleavage with secretase the phenotype of dystrophic mice, which assem- inhibitors may be a useful strategy for the ther- ble a defective basal lamina and have amyeli- apy of de-/dysmyelinating disorders. nated spinal roots (Madrid et al. 1975). Subse- quently, Schwann cells were shown to be unable to myelinate axons in cocultures in the absence Lgi4 and Adam22 of basal lamina assembly; addition of laminin Adam22 has recently emerged as a second, key to such cultures rescued myelination, providing axonal signal that promotes myelination. Ap- compelling support for its role (Bunge et al.

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Schwann Cell Myelination

1986). Finally, conditional knockout of laminin Gpr126 in Schwann cells results in aberrant ensheath- The Schwann cell adhesion G-protein-coupled ment and myelination in vivo (Chen and Strick- receptor (aGPCR), Gpr126 plays a key role dur- land 2003), effects that depend on a critical ing Schwann cell development by enhancing ra- threshold level of laminin (McKee et al. 2012). dial sorting (Mogha et al. 2013). Gpr126 is Other components of the matrix, notably the absolutely required for myelination (Monk collagens, also regulate Schwann cell myelina- et al. 2009). Recent studies strongly suggest tion (Chernousov et al. 2008). that Gpr126 is the long-sought receptor that Laminin itself is a trimer comprised of dif- regulates Schwann cell cAMP levels, an essential ferent a, b, and g chains. Laminin 2 (a2b1g1) is signal for Schwann cell myelination (Glenn and the principal endoneurial form; laminin 411 Talbot 2013b). Gpr126, which is coupled to and laminin 511 are minor forms (Chernousov both G and G , can directly elevate cAMP levels et al. 2008). Laminin 2, as well as the minor s i (Mogha et al. 2013) and activate PKA (Glenn isoforms, promote radial sorting and myelina- and Talbot 2013a). In agreement, Gpr126 null tion (Wallquist et al. 2005; Yang et al. 2005). Schwann cells are still able to myelinate axons if Several different laminin receptors expressed cAMP levels are elevated or PKA is activated on the abaxonal membrane, including b1 integ- (Glenn and Talbot 2013a; Mogha et al. 2013). rins and dystroglycan, transduce the effects of The ligand for Gpr126 has not yet been identi- laminin. Laminin promotes Schwann cell en- fied and could be either expressed by the axon sheathment and myelination via several cooper- and/or in the matrix. The latter possibility is ative mechanisms. These include establishing suggested by recent evidence that Gpr56, anoth- Schwann cell polarity (Bunge et al. 1986) akin er aGPCR, is activated by binding to collagen to its role in many cell types (Li et al. 2003), III (Luo et al. 2011a; Glenn and Talbot 2013b). activation of Schwann cell signaling pathways, Interestingly, once myelination is initiated, and organizing the abaxonal membrane, includ- Gpr126 and elevation of cAMP levels are no ing the Cajal bands (Court et al. 2011b). Finally, longer required for ongoing myelination or, the basal lamina may provide structural support like NRGI, for myelin maintenance (Glenn that anchors the abaxonal membrane and pre- and Talbot2013a,b). These latter results contrast vents the Schwann cell from migrating around with the requirement for ongoing expression the axon during myelination (Bunge et al. 1989). of the TFs, Krox20 and Sox10, to maintain my- Laminin regulates a wide array of signaling elin. Together, these results indicate that, once pathways to promote axon sorting, including myelination is established, ongoing TF expres- members of the Rho family of GTPases, notably sion becomes cell autonomous, presumably, via Rac1. Other downstream effectors implicated a feedforward cascade, which does not depend in radial sorting events include focal adhesion on extrinsic signals. kinase (FAK), which is present in the abaxonal compartment (Fernandez-Valle et al. 1998) and drives expansion of the Schwann cell pool es- sential for radial sorting (Grove et al. 2007). INTRACELLULAR SIGNALING PATHWAYS THAT REGULATE Integrin-linked kinase (ILK) also promotes ra- MYELINATION dial sorting and remyelination via an inhibition of Rho kinase (ROCK), thereby enhancing as- Significant effort, and progress, has focused on sembly of the actin cytoskeleton (see below) delineating the promyelinating signaling path- (Pereira et al. 2009; Montani et al. 2014). Recent ways downstream from these extrinsic signals studies also implicate the Jun activation do- that drive transcription, membrane biogene- main-binding protein 1 (Jab1) as an effector sis, and axon wrapping. Given its key role in of laminin signaling via a novel mechanism in- myelination, substantial attention has focused volving control of Schwann cell cycle and dif- on how NRG1 mediates its effects. Binding of ferentiation (Porrello et al. 2014). NRG1 to the erbB2/3 heterodimer activates a

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J.L. Salzer

series of canonical intracellular pathways down- TORC1 complex as it does in CNS myelination stream from many receptor tyrosine kinases (Bercury et al. 2014). (RTKs), that is, PI3K, PLC-g, and mitogen- PLC-g. The PLC-g pathway has also been activated protein kinase (MAPK) (Lemmon implicated as an important mediator of NRG1 and Schlessinger 2010). Each of these path- effects (Kao et al. 2009). Binding of NRG to erbB ways have been compellingly implicated in coreceptors activates PLC-g, resulting in elevat- Schwann cell development and differentiation ed intracellular calcium and activation of the downstream of NRG1 (Newbern and Birch- phosphatase calcineurin B, which, in turn, re- meier 2010); their precise role(s) in promoting sults in dephosphorylation of cytosolic nuclear Schwann cell differentiation and myelination factor of activated T cells (NFAT) proteins; are still emerging. these, then, accumulate in the nucleus and in- PI3K/Akt/mammalian target of rapamycin duce NFAT-mediated gene transcription (Kao (mTOR). The PI3K pathway plays a key role in et al. 2009). NFATc4 binds cooperatively with Schwann cell development (i.e., proliferation, Sox10 to the MSE of Krox20 (Kao et al. 2009; survival, and the initiation of myelination), Lazarevic et al. 2009); it also binds directly to the based on pharmacological inhibition and over- P0 promoter to drive P0 transcription. These expression studies (Maurel and Salzer 2000; studies also suggest that NFATis expressed early Ogata et al. 2006). Recent gain-of-function in the Schwann cell lineage and promotes axon studies extend these findings. Thus, activation sorting/ensheathment, in addition to its later of the PI3K pathway by conditional deletion of effects on myelin gene transcription (Kao et al. PTEN, a lipid phosphatase with opposing ef- 2009). fects, results in enhanced Schwann cell wrap- MAPK. Recent loss- and gain-of-function ping, even around collagen fibers, and hyper- studies in mouse models show that the MAPK myelination of axons (Goebbels et al. 2010). pathway is critical for promoting early Schwann Many of the effects of hyperactivation of PI3K cell differentiation and is a key signal that medi- in Schwann cells appear to be caused by activa- ates the promyelinating effects of NRG1. Thus, tion of the serine/threonine kinase Akt, and its Shp2, a phosphatase that activates MAPK, is activation of mTOR. Thus, treatment of mice required for normal Schwann cell differentia- with activated PI3K pathway with rapamycin tion and myelination; conditional inactivation reverses many of these hyperwrapping effects of Shp2 phenocopies that of the erbB2 knockout (Goebbels et al. 2012; E Domenech, H Baloui, (Grossmann et al. 2009). Likewise, conditional and JL Salzer, in prep.). Conditional inactivation ablation of Gab1, a scaffolding protein required of mTOR in embryonic Schwann cells results in for RTK signaling, results in reduced Erk acti- thin, short myelin sheaths, providing direct ev- vation and substantial hypomyelination (Shin idence for its key role in PNS myelination (Sher- et al. 2014). Direct evidence for the role of the man et al. 2012a). mTOR activation is strongly MAPK pathway was shown by combined, ge- driven by NRG and, accordingly, is initially lo- netic ablation of Erk1/2 during development, calized along sites that contact the axon (Heller which results in impaired Schwann cell differen- et al. 2014). These latter results suggest that the tiation and myelination (Newbern et al. 2011). hypomyelination observed in mice haploinsuf- Finally, in a recent study (Sheean et al. 2014), ficient for NRG1 (Michailovet al. 2004; Taveggia conditional expression of an “activated” form of et al. 2005) is, in part, a result of reduced mTOR MAPK (Mek1) in Schwann cells results in a sus- activity. The precise role(s) of mTOR during tained increase in the amount of myelination. Of myelination are yet to be established, but seem note,transgenicexpressionofthisactivatedMek1 likely to reflect its key role in regulating protein in Schwann cells deficient in erbB3 or Shp2, res- translation (Laplante and Sabatini 2013), in- cues Schwann cell proliferation, migration, and cluding, potentially, of proteins required for myelination of axons (Sheean et al. 2014). myelination. Ongoing studies should also clarify These results compellingly implicate MAPK whether mTOR mediates its effects via the as a crucial signaling pathway downstream from

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Schwann Cell Myelination

Nrg1 in promoting Schwann cell myelination. nisms have recently begun to emerge. In partic- MAPK activates the promyelinating TF YY1 ular, as development proceeds, promyelinating (He et al. 2010). However, the promyelinating signaling components of the NRG1/erbB signal- effects of MAPK activation may depend sub- ing pathwayare down-regulated and, conversely, stantially on its stimulation of mTOR-depen- negative regulators, which function as “brakes” dent and -independent protein translation, on signaling, are up-regulated. NRG1 activity is which normally subsides at the onset of myeli- itself subject to negative regulation, in part, via nation. The ability of this single pathway to res- a neuron-autonomous effect of vimentin (Tri- cue myelination was unexpected, given the ab- olo et al. 2012). NRG1 activity is also down- sence of NRG1-dependent activation of PI3K regulated as a consequence of TACE cleavage and PLC-g. It suggests that either MAPK can (La Marca et al. 2011). In addition, Schwann indirectly activate these pathways or that other cell expression of erbB2 (Cohen et al. 1992; Jin extrinsic signals activate these pathways at suf- et al. 1993) and Akt (Heller et al. 2014; Sheean ficient levels for myelination to ensue even in et al. 2014) are markedly down-regulated with the absence of erbB3 signaling. myelination. Elucidating whether other pro- cAMP. This intracellular signal is known to myelinating signals are similarly down-regulat- promote and maintain the myelinating pheno- ed will be of future interest. type of Schwann cells (Stewart et al. 1991; Monje Negative regulation of the PI3K/Akt/ et al. 2010). It appears to do so via a number mTOR pathway also limits the extent of myeli- of mechanisms. cAMP converts the response nation. PTEN is recruited to the adaxonal com- of Schwann cells to NRG1 from proliferation partment by interactions with Dlg1, resulting in to differentiation (Arthur-Farraj et al. 2011). It down-regulation of (NRG1-dependent) PI3K increases the expression of the promyelinating activation. However, loss of Dlg1 results in only TF,Pou3f1 (Monuki et al. 1989), and in cultured a modest, transient hypermyelination (Cotter cells was shown to cooperate with NFATto drive et al. 2010), indicating other mechanisms also Krox20 expression (Kipanyula et al. 2013). exist. Among these are REDD1, which inhibits cAMP activates cAMP-dependent PKA, which mTOR activity. Loss of REDD1 results in en- promotes Schwann cell myelination in cocul- hanced TORC1 activation and modest, sus- tures (Howe and McCarthy 2000) and Gpr126- tained hypermyelination (Noseda et al. 2013). deficient zebrafish (Glenn and Talbot 2013a). Unexpectedly, the basal lamina, which is re- PKA phosphorylates and activates several TFs. quired for initial differentiation and radial sort- Among these are NF-kB and members of the ing by Schwann cells, also limits the amount of CREB family including CREB1, CREM, and myelin that forms. Such an inhibitory role was ATF1, which bind as dimers to cAMP-respon- suggested by older studies of the a2 and a4 sive elements (CREs) (Tasken and Aandahl laminin chain knockouts. Although the most 2004). Studies in myelinating cocultures suggest striking defects in these knockout mice was a that induction of Schwann cell differentiation by failure of radial sorting and myelin initiation, cAMP and NRG1 require the activity of CREB nerves also displayed examples of hypermyeli- family members (Arthur-Farraj et al. 2011). Fu- nated fibers and polyaxonal myelination, re- ture studies that directly target the activity of spectively (Bradley and Jenkison 1973; Wall- CREB TFs in vivo will establish their role more quist et al. 2005). Hypermyelination of axons precisely in myelination. and polyaxonal myelination have also been ob- served in human dystrophic nerves (Di Muzio et al. 2003) and mice with conditional ablation Termination of Myelination of dystroglycan (Saito et al. 2003) or periaxin The tight correlation of myelin sheath thickness (Gillespie et al. 2000). Recent studies also show to axon diameter suggests that there are controls that laminin–a6b4 interactions in the abaxonal that limit myelin thickness. A key question is compartment activate Sgk1, which transiently what terminates myelination? Some mecha- inhibits myelination (Heller et al. 2014). More

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J.L. Salzer

sustained hypermyelination is observed in mice wrapping of the Schwann cell plasma mem- lacking collagen VI in the basal lamina, accom- brane around the axon (Geren 1954). The my- panied by a significant reduction in g ratios elin sheath is initially loosely spiraled for the (Chen et al. 2014). Interestingly, there are sig- first few turns, then compacts with up-regula- nificant increases in the levels of FAK, Akt, and tion of myelin proteins, notably P0 (Kidd et al. Erk signaling in the nerves from these mice 2013). In a classic study, Bunge et al. (1989) (Chen et al. 2014). The mechanism(s) by which provided compelling evidence that spiral wrap- collagen VI down-regulates these signaling ping results from circumnavigation of an inner pathways is not known, but has important ther- turn around the axon rather than by migration apeutic implications. of the Schwann cell soma/nucleus in the outer compartment around the sheath. This model Activation of Signaling Pathways Can Also was also suggested by earlier studies in which Drive Dedifferentiation developing nerves in tadpole tails were live im- aged (Speidel 1964). A current paradox is that high-level activation The innermost turns are likely to be initially of signaling pathways that promote myelination narrower than the full expanse of the inter- can, under some circumstances, inhibit myeli- node, as suggested by older electron microscopy nation and even result in frank demyelination. (EM) studies (Webster 1971), and expand later- This was originally shown in myelinating cocul- ally as the sheath matures. This interpretation is tures in which addition of type II NRG1, but not strongly supported by staining for the parano- other NRG1 isoforms, results in substantial de- dal marker Caspr, which delineates the lateral myelination (Zanazzi et al. 2001). Demyelina- edge of the Schwann cell. At the onset of myeli- tion was also observed in vivo in transgenic nation, Caspr is initially concentrated in a loose overexpressors of this NRG isoform (Huijbregts spiral that extends into the internode; this spiral et al. 2003). Subsequently, studies suggested that progressively concentrates into a tight band as this dedifferentiation is attributable to activa- myelin matures (Pedraza et al. 2001). Compel- tion of the MAPK and Jun kinase pathways, ling, direct support for this model was provided and this activation may function to reprogram by live imaging and quantitative morphometry the Schwann cell during the injury response of the developing, CNS myelin sheath (Snaidero (Parkinson et al. 2008; Napoli et al. 2012). In- et al. 2014; Simons and Nave 2015). deed, an emerging number of growth factors Thus, expansion of the myelin sheath is like- and signaling pathways that negatively regulate ly to occur along the inner turn and at the lateral myelination, including the Notch pathway margins of the sheath, which function as the (Woodhoo et al. 2009), have been identified. equivalent of leading edges of the expanding The normal role of these negative regulators sheath (Kidd et al. 2013). Growth of the inner may be in fine-tuning the onset of myelination membrane requires it to intercalate between the during development and promoting the regen- existing inner membrane and the axon (see Fig. erative phenotype of the Schwann cells follow- 5), disrupting existing interactions between the ing injury, as discussed in Jessen et al. (2015). axon and Schwann cell. Whether expansion of Such dedifferentiative pathways may also con- the inner turn is guided by interactions with the tribute to demyelination in pathological set- axon (heterotypic interactions), the glial mem- tings and, as such, offer the potential for the brane (homotypic interactions), or both is not development of rational therapeutic approaches yet known. New components of the membrane to demyelinating neuropathies. are added in the abaxonal and perinuclear re- gion (Gould 1977) and, potentially, within the THE MORPHOGENESIS OF THE MYELIN paranodes (Gould and Mattingly 1990); these SHEATH components then diffuse throughout the form- Early electron microscopic studies established ing myelin sheath. This occurs much more rap- the myelin sheath forms as the result of spiral idly for membrane lipids than myelin proteins

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Schwann Cell Myelination

(Gould 1977). Interestingly, even after compact that establish the proper stoichiometry of myelin has formed, the sheath rapidly expands these myelin components. Indeed, alterations and its internal circumference continues to in- in the stoichiometry of myelin proteins, such crease to accommodate radial expansion of as PMP22 and P0 resulting from haploinsuffi- the axon (Webster 1971). Together, these results ciency or overexpression, result in genetic neu- suggest that the myelin sheath conforms to the ropathies (Suter and Scherer 2003). Production classical model of a fluid mosaic membrane, of this huge expanse of membrane imposes sig- with diffusion potentially enhanced by its nificant stresses on the Schwann cell, including high-lipid content. in the ER, rendering them especially vulnerable A related question is what determines the to proteins that fold or traffic aberrantly. This is length of the myelin internode during develop- evident in the pathology of many inherited ment? Together with axon diameter and myelin neuropathies (D’Antonio et al. 2009, 2013). thickness, internode length is a key determinant of nerve conduction velocity (Waxman 1980). RADIAL SORTING AND MYELINATION: Much of the expansion of the internode during ROLE OF THE ACTIN CYTOSKELETON development is thought to result from axon elongation dictated by growth of the developing A long-standing question is what drives the limbs (Hildebrand et al. 1994). Experimental circumferential expansion of the Schwann cell manipulations that gradually elongate limbs membrane that propels radial sorting and mye- result in increased internode length (Abe et al. lination? In motile cells, branched and cross- 2004; Simpson et al. 2013), whereas impairment linked networks of actin provide the major of limb development reduces internode length engine for movement of the lamellipodial mem- (Hildebrand et al. 1989). There is some modi- brane by polymerizing against it (Blanchoin fication of internode length that results from et al. 2014). Likewise, radial sorting, wrapping, alterations in the numbers of Schwann cells and elongation of the Schwann cell along the available for myelination, with a reduction or axon rely on the precise spatial and temporal an increase in Schwann cells resulting in an in- remodeling of the actin cytoskeleton along the crease or decrease of internode length, respec- lateral and inner membrane. F-actin is present in tively (Hildebrand et al. 1994). In the normal, essentially all cytoplasmic compartments of my- adult peripheral nerve, internode lengths are elinating Schwann cells, that is, the Schmidt– optimized for their role in saltatory conduc- Lanterman incisures, the periaxonal membrane, tion (Simpson et al. 2013). Conversely, the short the paranodes, and the outer and inner mesaxon internodes, characteristic of remyelinated seg- and paranodal loops (Trapp et al. 1989)—sites ments (Scherer and Salzer 2000), likely contrib- of morphogenesis during myelination. Inhibi- ute to reduced nerve conduction velocities. tion of actin assembly blocks myelination in co- Such short, remyelinated segments are thought culture models (Fernandez-Valle et al. 1997). to result from myelin formation around adult Interestingly, the effects of inhibiting actin as- axons that are no longer actively elongating. sembly are dose dependent with high doses Finally, formation of the myelin sheath re- blocking all ensheathment and intermediate quires dramatic expansion of the plasma mem- doses permitting axon segregation, but not my- brane. By some estimates, myelinating Schwann elin progression (Fernandez-Valle et al. 1997). cells may generate up to 20 mm2 of membrane Similarly, inhibition of myosin II in cocultures around the largest axons—some 2000 times blocks axon sorting and myelination (Wang that of a typical epithelial cell (Kidd et al. et al. 2008). Unexpectedly, inhibition of myosin 2013). The rapid membrane production that II appears to potentiate CNS myelination, indi- occurs during myelination requires coordina- cating that myelination in the PNS and CNS is tion of gene transcription, protein translation, mechanistically distinct (Wang et al. 2008). directed trafficking of myelin components to Consistent with the key role of the actin/ sites of membrane addition, and mechanisms myosin cytoskeleton in myelin morphogenesis,

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an increasing number of regulators of actin as- One key effector is the neuronal Wiskott–Al- sembly have been implicated in Schwann cell drich syndrome protein (N-WASP), which is myelination (Fig. 5). Among these are Rho, downstream from Rac1 and cdc42; it is known Rac1, and cdc42, foundational members of the to bind to the Arp2/3 complex to nucleate new small Rho GTPase familyof proteins. Rho family branched arrays of actin filaments (Burianek members are master regulators of cytoskeleton and Soderling 2013). N-WASP localizes to the dynamics that control a wide array of morpho- leading edge of Schwann cell processes (Bacon genetic events; they function as molecular et al. 2007); its expression peaks early postnatal- switches, cycling between inactive guanosine ly (Jin et al. 2011). Pharmacological inhibition diphosphate (GDP)-bound and active guano- of N-WASP in Schwann cell cultures prevents sine triphosphate (GTP)-bound states (Heas- activation of the Arp2/3 complex and impairs man and Ridley 2008; Hall 2012). Conditional myelination in cocultures (Bacon et al. 2007). inactivation of Rac1 or cdc42 during Schwann Conditional inactivation of N-WASP markedly cell development results in impaired axon sort- delays sorting and profoundly impairs myelin ing, delayed myelination, and significant hypo- wrapping (Jin et al. 2011; Novak et al. 2011); myelination (Benninger et al. 2007; Nodari et the few cells that myelinate have markedly short- al. 2007). Loss of cdc42 also impairs Schwann er internodes, indicating that elongation and cell proliferation (Benninger et al. 2007) and the spiral membrane wrapping share similar actin function of the Par3 polarity complex (Gold- machinery. Interestingly, Schwann cells are still stein and Macara 2007), both of which are likely able to initiate the transcriptional program of to affect radial sorting. Interestingly, conditional myelination in mutants, indicating that myelin knockouts of Rac1 and cdc42 have distinct and morphogenesis and transcriptional activation less-severe effects on oligodendrocyte myelina- are not obligately linked. N-WASPis an effector tion (Thurnherr et al. 2006), further underscor- of cdc42 (Rohatgi et al. 1999) and, thus, po- ing differences between PNS and CNS myelina- tentially links NRG1-dependent activation of tion. Rho and its key effector ROCK promote cdc42 to actin assembly at the leading edge of radial sorting (Pereira et al. 2009) and the coor- the myelinating Schwann cell. Arguing against dinated progression of the inner turn of the my- this model, however, maximal N-WASP ex- elin sheath around the axon at the onset of mye- pression is present in the abaxonal compart- lination via regulation of actomyosin assembly ment (Jin et al. 2011). Other studies suggest (Melendez-Vasquez et al. 2004). that cdc42 may also promote radial sorting, in Multiple extrinsic signals have been impli- part, via NF2/merlin (Guo et al. 2013). Finally, cated in activating these various GTPases. cdc42 recent studies suggest that the Rho/ROCK path- is activated in cultured Schwann cells by soluble way promotes lamellipodia by a separate, paral- NRG1 (Benninger et al. 2007); the importance lel pathway involving myosin light-chain kinase of NRG1 as an activator of cdc42 in vivo is not (MLCK) and activation of myosin II and by yet established. In contrast, Rac1 is activated activating the actin-binding protein profilin1; downstream from laminin/b1 integrin signal- this latter pathway is negatively regulated by ing (Benninger et al. 2007; Nodari et al. 2007). ILK (Montani et al. 2014). Indeed, overexpression of Rac1 partially rescues In addition to proteins that promote its the phenotype of Schwann cell conditional b1- assembly and branching, depolymerization of integrin nulls (Nodari et al. 2007). Activation the actin cytoskeleton is also actively regulated, of Rac1 downstream from integrins involves including by the actin-severing protein cofilin. the lymphoid cell kinase (Lck) in a pathway NRG1 activates cofilin via the cofilin-phospha- that also includes paxillin and CrkII (Ness tase Slingshot1, which is activated by translo- et al. 2013). cation to and association with F-actin at the The pathways downstream from these leading edge of lamellipodia (Nagata-Ohashi GTPases, and how they regulate the cytoskele- et al. 2004). In agreement, NRG1 promotes ton, are complex and incompletely understood. translocation of nonphosphorylated cofilin to

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the leading edge of cultured Schwann cells 1979; Windebank et al. 1985; Waegh et al. 1992), (Sparrow et al. 2012). Further, knockdown of which, in turn, increases nerve conduction ve- cofilin1 in cultured synaptonemal complexes locity (Gasser and Grundfest 1939). Radial ex- (SCs) blocked their engagement or alignment pansion is locally regulated and most evident along axons, assembly of the basal lamina, and along the internode of large PNS fibers. Thus, ability to myelinate (Sparrow et al. 2012). the diameter of the axon in the paranodal and Taken together, these findings suggest that nodal regions may be as little as 15%–20% of actin is dynamically and obligately regulated that of the internode (Berthold 1996). Interest- during axon segregation and myelination. Based ingly, the reduced diameter of the axon at the on ligand activation and localization stud- node and paranodes may also enhance conduc- ies, NRG1/erbB activate cofilin and cdc42 at tion velocity by reducing the surface area and, the leading edge of the adaxonal membrane, thereby, the capacitance of the nodal axolemma leading to a cycle of actin depolymerization (Halter and Clark 1993). and N-WASP-dependent assembly, respectively; The signals from myelin, which drive radial these results are consistent with actin treadmil- expansion, remain incompletely understood. ling known to underlie lamellipodial extension Their highly local nature is apparent in the re- in most cells (Pollard and Borisy 2003). In ad- duced diameter of the axon present immedi- dition, Rac1 and Rho/ROCK act in the abaxo- ately underneath regions of noncompact myelin nal compartment downstream from laminin/ (e.g., Schmidt–Lanterman incisures) (Price et b1 integrin to drive actinomyosin activity re- al. 1993). One mechanism involves MAG, quired for radial sorting. Future studies to fur- which is required for full phosphorylation of ther delineate the spatial and temporal regula- neurofilament subunits (Yin et al. 1998) and tion of these diverse actin regulatory pathways, thereby regulates the packing of the neurofila- and identify additional effectors, will provide ment cytoskeleton (Waegh et al. 1992; Cole et al. important insights into both myelin formation 1994). Regions of greatest expansion are associ- and, potentially, prospective remodeling of PNS ated with more substantial neurofilament phos- myelin sheaths in the adult and following injury. phorylation and a lower density of neurofila- ments/square area (Price et al. 1993). It has also long been known that myelination FUNCTIONAL CONSEQUENCES regulates axonal transport. The rates of slow and OF MYELINATION ON THE AXON fast axonal transport are reduced in the nodal Myelinating Schwann cells profoundly reorga- and paranodal regions (Waegh et al. 1992; Zim- nize the underlying axon, including its domain mermann 1996; Salzer 2003). This is evident by organization, the axonal cytoskeleton, and its the accumulation of .90% of the membranous metabolic requirements. As a consequence, the organelles in the nodes and paranodes of large, axon is especially vulnerable to loss of myelin, myelinated axons (Berthold et al. 1993). Direct which significantly contributes to the morbidity support for a reduction in transport rates was of dysmyelinating and demyelinating disorders. provided by live imaging (Cooper and Smith The role of myelin on the domain organization 1974) and accumulation of metabolically la- of axons is considered in detail elsewhere in the beled glycoproteins at this site (Armstrong literature (Rasband and Peles 2015). Here, we et al. 1987). The mechanism(s) responsible for briefly highlight other effects of myelination on the reduction of transport in the nodal/parano- the axon. dal region are not known, but may result from the constricted axon diameter at this site (Zim- mermann 1996) or potentially alterations of Local Regulation of the Axonal Cytoskeleton microtubule–motor interactions. EM tomog- and Transport raphy suggests that the paranodes may directly Myelinating Schwann cells promote the radial regulate vesicle transport (Nans et al. 2011). The expansion of the underlying axon (Aguayo et al. accumulation of mitochondria and vesicles in

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(Caspr) knockout mice (Einheber et al. 2006; from the Schwann cell to the axon. This possi- Garcia-Fresco et al. 2006) also support a role bility was suggested in older studies analyzing for the paranodes in regulating transport. the squid giant axon (Lasek et al. 1977; Cutillo et al. 1983) and has been supported by newer, genetic labeling strategies, which are coupled to Metabolic Support and Transfer analysis of transected axons to eliminate the of Macromolecules soma as a source of components. These recent studies suggest that messenger RNA (mRNA) Peripheral nerves can be 100 feet or more in (Sotelo et al. 2013) and ribosomes (Court length in the blue whale and may have been as et al. 2008) are transferred from the Schwann long as 200 feet in the largest of the sauropods, cell to the axon during injury (Twiss and Fain- based on fossil records (Wedel2011). This enor- zilber 2009) and regeneration (Court et al. mous expanse of axon underscores the need 2011a). Transfer from the Schwann cell to the for and, likely, ancestral role of (myelinating) axon appears to be concentrated at the incisures Schwann cells, that of the trophic support of and in the nodal region and requires actin and long axons (Nave 2010). myosin (Va) (Sotelo et al. 2013). Future studies Schwann cells have long been known to that address the functional significance of this provide trophic support for axons (Varon and transfer and the extent to which transfer also Bunge 1978). This requirement is strikingly ev- occurs during nerve development and/or in ident in the developmental loss of PNS neu- the uninjured adult PNS will be of considerable rons/axons in mutant mice that lack Schwann interest. cells (Birchmeier 2009). The focus of current studies of how myelinating glia maintain axons CONCLUSIONS has shifted from growth factors, for example, neurotrophic factors, to metabolism. The axon There has been gratifying progress in our under- is largely shielded from the extracellular space standing of Schwann cell myelination, includ- along its entire length by the overlying myelin ing identification of key extrinsic signals, the in- sheath, except at the nodes of Ranvier. This sug- tracellular pathways they activate, and the tran- gests that myelinating glia release metabolites scriptional and epigenetic programs that co- that are transported into and sustain the metab- operate to promote the myelinating phenotype. olism of axons in both the CNS and PNS. This Important questions remain. Among these is has been recently shown in the case of oligoden- how the transcriptional program is coupled to drocytes, which provide lactate as a source of the morphogenesis of the myelin sheath? Fre- energy to axons and thereby prevents axonal quently, an arrest in myelination caused by tran- degeneration (Funfschilling et al. 2012; Lee scription is associated with an arrest of myelin et al. 2012). Similarly, disruption of mitochon- wrapping, particularly, at the promyelinating drial function in Schwann cells has, as its major stage. This suggests that these processes are cou- pathological feature, the progressive degenera- pled byan as-yet unknown mechanism to ensure tion of small fiber and myelinated axons (Viader that membrane expansion is coordinated to et al. 2011). In the latter case, this is a result of a wrapping; local translational control may also shift in Schwann cell lipid oxidation that culmi- be involved. nates in release of toxic acylcarnitines with re- With the identification of multiple extrinsic sultant axonal degeneration (Viader et al. 2013). regulators of Schwann cell myelination, a chal- Together, these findings have important impli- lenge is to delineate the spatiotemporal activity cations for the axonal loss observed in myelin of their downstream signaling pathways and disorders. effectors, determine the effects of combinatori- Recent studies have also revived interest in al signaling, and elucidate further the mecha- the provocative notion that macromolecules, nisms that terminate their activity. Axonal and notable RNA and ribosomes, are transferred matrix signals activate pathways in the adaxonal

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Schwann Cell Myelination

and abaxonal compartments, respectively. How been supported by the National Institutes of are these pathways integrated? In particular, Health and the National Multiple Sclerosis So- how are the signals from both compartments ciety. The author regrets any omissions in citing coordinated to regulate the axonal cytoskeleton relevant publications of other colleagues in the remodeling during myelination? The extent to myelin field. which extrinsic signals terminate ongoing mye- lination and/or inhibit myelination of small fi- bers is also not well understood. REFERENCES Finally, whether axonal activity regulates ÃReference is also in this collection. myelin formation by Schwann cells, their tro- Abe I, Ochiai N, Ichimura H, Tsujino A, Sun J, Hara Y.2004. phic (reciprocal) support of axons, and the Internodes can nearly double in length with gradual plasticity and maintenance of myelin in the elongation of the adult rat sciatic nerve. J Orthop Res adult are important unanswered questions 22: 571–577. Aguayo AJ, Bray GM, Perkins SC. 1979. Axon-Schwann cell (Samara et al. 2013). Recent studies of CNS relationships in neuropathies of mutant mice. Ann NY myelination indicate a surprising amount of Acad Sci 317: 512–531. ongoing myelination in the adult (Young et Armstrong R, Toews AD, Morell P. 1987. Axonal transport al. 2013) and suggest that neural activity and through nodes of Ranvier. Brain Res 412: 196–199. experience may be important regulators of ol- Arthur-Farraj P, Wanek K, Hantke J, Davis CM, Jayakar A, Parkinson DB, Mirsky R, Jessen KR. 2011. Mouse igodendrocyte myelination (Liu et al. 2012; Schwann cells need both NRG1 and cyclic AMP to mye- Makinodan et al. 2012; Gibson et al. 2014). linate. Glia 59: 720–733. Schwann cells are known to express a variety Atanasoski S, Scherer SS, Sirkowski E, Leone D, Garratt AN, Birchmeier C, Suter U. 2006. ErbB2 signaling in Schwann of proteins that allow them to detect signals cells is mostly dispensable for maintenance of myelinated produced by electrically active axons (Samara peripheral nerves and proliferation of adult Schwann cells et al. 2013). In the PNS, older coculture stud- after injury. J Neurosci 26: 2124–2131. ies suggest that activity may indeed regulate Bacon C, Lakics V, Machesky L, Rumsby M. 2007. N-WASP regulates extension of filopodia and processes by oligo- Schwann cell myelination (Stevens et al. 1998; dendrocyte progenitors, oligodendrocytes, and Schwann Stevens and Fields 2000). More recent in vivo cells—Implications for axon ensheathment at myelina- analysis also suggests a role of activity in myelin tion. Glia 55: 844–858. maintenance (Canu et al. 2009). Direct analy- Balice-Gordon RJ, Bone LJ, Scherer SS. 1998. Functional gap junctions in the Schwann cell myelin sheath. J Cell Biol sis of whether there is ongoing myelin remod- 142: 1095–1104. eling in the adult PNS, including live imaging Beirowski B, Gustin J, Armour SM, Yamamoto H, Viader A, with methods and genetic strategies to modu- North BJ, Michan S, Baloh RH, Golden JP,Schmidt RE, et al. 2011. Sir-two-homolog 2 (Sirt2) modulates peripheral late activity during development in vivo, will be myelination through polarity protein Par-3/atypical pro- of considerable interest for future investigation. tein kinase C (aPKC) signaling. Proc Natl Acad Sci 108: E952–E961. Benninger Y, Thurnherr T, Pereira JA, Krause S, Wu X, ACKNOWLEDGMENTS Chrostek-Grashoff A, Herzog D, Nave K-A, Franklin RJ, Meijer D, et al. 2007. Essential and distinct roles for cdc42 This review is dedicated to three esteemed col- and rac1 in the regulation of Schwann cell biology during leagues and friends: Dr. Marie Filbin, Dr. David peripheral nervous system development. J Cell Biol 177: 1051–1061. Colman, and Dr. Jack Griffin. Their studies Bercury KK, Dai J, Sachs HH, Ahrendsen JT, Wood TL, greatly contributed to our understanding of Macklin WB. 2014. Conditional ablation of raptor or ric- myelin biology; their bonhomie and enthusi- tor has differential impact on oligodendrocyte differen- asm fostered today’s community of glial biolo- tiation and CNS myelination. J Neurosci 34: 4466–4480. Bermingham JR Jr, Shearin H, Pennington J, O’Moore J, gists. The author gratefully acknowledges his Jaegle M, Driegen S, van Zon A, Darbas A, Ozkaynak own laboratory colleagues, past and present, E, Ryu EJ, et al. 2006. The claw paw mutation reveals a for their many contributions to studies cited role for Lgi4 in peripheral nerve development. Nat Neu- here, Jill Gregory for outstanding artwork, and rosci 9: 76–84. Berthold CH. 1996. Development of nodes of Ranvier in Bob Gould and John Svaren for helpful discus- feline nerves: An ultrastructural presentation. Microsc sions. Studies from the author’s laboratory have Res Tech 34: 399–421.

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J.L. Salzer

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26 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a020529 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press

Schwann Cell Myelination

James L. Salzer

Cold Spring Harb Perspect Biol published online June 8, 2015

Subject Collection Glia

The Nodes of Ranvier: Molecular Assembly and Oligodendrocyte Development and Plasticity Maintenance Dwight E. Bergles and William D. Richardson Matthew N. Rasband and Elior Peles Microglia in Health and Disease Oligodendrocytes: Myelination and Axonal Richard M. Ransohoff and Joseph El Khoury Support Mikael Simons and Klaus-Armin Nave The Astrocyte: Powerhouse and Recycling Center Drosophila Central Nervous System Glia Bruno Weber and L. Felipe Barros Marc R. Freeman Microglia Function in Central Nervous System Perisynaptic Schwann Cells at the Neuromuscular Development and Plasticity Synapse: Adaptable, Multitasking Glial Cells Dorothy P. Schafer and Beth Stevens Chien-Ping Ko and Richard Robitaille Transcriptional and Epigenetic Regulation of Astrocytes Control Synapse Formation, Function, Oligodendrocyte Development and Myelination in and Elimination the Central Nervous System Won-Suk Chung, Nicola J. Allen and Cagla Eroglu Ben Emery and Q. Richard Lu Origin of Microglia: Current Concepts and Past Schwann Cell Myelination Controversies James L. Salzer Florent Ginhoux and Marco Prinz Glia Disease and Repair−−Remyelination Schwann Cells: Development and Role in Nerve Robin J.M. Franklin and Steven A. Goldman Repair Kristján R. Jessen, Rhona Mirsky and Alison C. Lloyd Astrocytes in Neurodegenerative Disease Perineurial Glia Hemali Phatnani and Tom Maniatis Sarah Kucenas

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